Project Summary Swallowing difficulties are extremely common and result in a substantial reduction in the quality of life for patients regardless of the cause. Unfortunately, our understanding regarding the pathophysiologic explanation for symptom generation is poor. In contemplating the occurrence of esophageal symptoms during swallowing it is logical to focus attention on intrabolus pressure (IBP), as this is the primary force that empties the esophagus. Intrabolus pressure is dependent on a number of factors; however, the primary determinant is EGJ compliance as flow out of the esophagus is highly dependent on EGJ diameter. The hypothesis for this proposal focuses on the relationship between IBP and EGJ compliance as it relates to symptoms of dysphagia and chest pain. Thus, the goals of this proposal are:1) to define the physiologic relationship between IBP and EGJ compliance, 2) determine the correlation between symptom severity and IBP abnormalities, and 3) study the relationship between esophageal sensitivity and IBP in symptom generation. In order to accomplish the above goals, a comprehensive set of anatomical and physiological studies focused on measuring intrabolus pressure, peristaltic integrity, esophageal wall thickness and compliance of the EGJ to elucidate the role of EGJ compliance and intrabolus pressure in generating esophageal symptoms during swallowing will be performed. EGJ compliance will be determined using impedance planimetry to create a multidimensional rendering of EGJ geometry, while intrabolus pressure and peristaltic integrity will be assessed using a solid-state HRM system. Impedance planimetry will also be used to assess esophageal sensitivity and quality of life and psychosocial questionnaires will also be incorporated into the analysis as these are important variables in symptom perception. We have validated several new techniques to measure the mechanically relevant variables of bolus transit. These physiologic and mechanical variables will be used to assess the correlation between symptom severity and the mechanics of esophageal emptying. In addition, statistical models will be developed to help predict the effect EGJ compliance has on IBP. The clinical relevance of these mechanical variables will be validated in a study assessing the effect of therapy focused on increasing EGJ compliance and reducing IBP on symptom perception. Patients will have esophageal sensitivity analysis before and after therapy to control this variable in the analysis. Our ultimate goal for this proposal is to develop and validate novel analysis paradigms that will focus on the mechanical relationship between esophageal sensation and intrabolus pressure. These new analysis techniques will improve diagnostic classification of relevant esophageal motor disease and also help determine which patients may benefit from treatment focused on reducing intrabolus pressure.